L-(−)-Carnitine is a vitamin-like nutrient that is essential for energy production and fat metabolism in the physiological systems of birds, fish, and mammals. L-Carnitine has the molecular formula:
L-carnitine is supplied to the body through both endogenous synthesis (about 25% of the adult daily requirement) and food intake (about 75% of the adult daily requirement). The main dietary source of L-carnitine is meat; beef and lamb provide the most dietary L-carnitine. (Fruits and vegetables provide only traces of L-carnitine.) Within the human body, the major sites of L-carnitine biosynthesis are the liver and kidney, as well as the brain and testes. Biosynthesis requires lysine, methionine, vitamin C, iron, vitamin B6, and niacin.
L-(−)-Carnitine functions as a requisite mediator of acyl transport and accepts acyl groups from a variety of acylCoA derivatives in cells and tissues throughout the body. In humans, the transport activity of L-carnitine is particularly important in working muscle, for example, in the skeletal muscles and the heart. Both types of tissues are dependent on fatty acid metabolism for energy supply, and L-carnitine mediates the translocation of fatty acyl groups across mitochondrial membranes to the sites of oxidation in the mitochondria. In addition, L-carnitine shuttles short chain fatty acids from inside the mitochondria to the cytosol. Other physiological roles of L-carnitine include mitochondrial long-chain fatty acid oxidation, buffering of the mitochondrial acyl CoA/CoA couple, scavenging acyl groups, peroxysomal fatty acid oxidation, branched-chain amino acid oxidation, and membrane stabilization.
An incomplete diet, physiological stress situations, such as exercise or pregnancy, and metabolic dysfunction, in particular, lipid disorders or diseases of the liver and kidney, create a need for L-carnitine supplementation. In addition, L-carnitine is an essential nutrient for infants, since neonates and young children lack the capacity to synthesize L-carnitine in the quantities that are needed for optimal development.
Because L-carnitine functions as a requisite mediator of acyl transport in the body, an L-carnitine deficiency is a serious physiological disorder. Individuals who suffer from L-carnitine deficiency are afflicted with muscle weakness (myasthenia), accompanied by an accumulation of lipids in specific types of muscle fibers. Severe L-carnitine deficiency may present as myasthenia gravis. Individuals who suffer from systemic L-carnitine deficiency and also secondary L-carnitine deficiency associated with organic acidemias may experience vomiting, stupor, confusion and in severe or prolonged occasions of systemic L-carnitine deficiency accompanied by stressful stimuli, coma in encephalopathic episodes.
It is known that L-carnitine is very hygroscopic. The hygroscopicity of L-carnitine causes a lack of storability of the solid substance and of simple powder mixtures prepared therefrom, and causes problems such as inadequate flowability during further formulating, processing, and manufacturing of orally administrable dosage forms of pure solid L-carnitine or powdered mixtures containing L-carnitine for use in food, nutritional or dietary supplements for humans or other mammals, animal feed or dietary supplements, or drugs for human or veterinary use. However, oral dosage forms represent the preferred dosage forms, inasmuch as they make it particularly easy for users to take the active ingredient and comply with optimal dosage regimens.
Further, it is known that L-carnitine exhibits a distinctly objectionable malodor and a distinctly distasteful taste after ingestion. The noxious odor and taste render ingestion of oral dosage forms of L-carnitine difficult and interfere with compliance to optimal dosage regimens. Thus, there is a significant unmet need for a form of L-carnitine that is free from noxious odor or taste.
Calcium (Ca2+) is the major extracellular divalent cation. Ca2+ is essential for bone development and maintenance and functions in many other important physiological processes, including neuronal excitability, neurotransmitter release, muscle contraction, membrane integrity, and blood coagulation. In addition, Ca2+ serves a second messenger function for the actions of many hormones.
Exogenous Ca2+ is conventionally supplied by ingestion of oral compositions containing calcium salts. Among the conventionally used calcium salts are calcium carbonate, calcium acetate, calcium gluconate, calcium citrate, calcium chloride, and calcium phosphate. Many of the conventional calcium salts have objectionable tastes; ingestion of calcium acetate, for example, causes regurgitation of acetic acid and “vinegar breath.” Other conventional calcium salts, such as calcium carbonate, for example, are “chalky” and have widely variable bioavailability through absorption from the gastrointestinal tract. Further, calcium carbonate that is prepared from limestone contains traces of toxic metals such as lead and aluminum. Thus, there is a significant unmet need for a Ca2+ salt that is free from noxious taste, objectionable after-effects of ingestion, and toxins.
There is now an extensive body of literature, including patents, disclosing the production of allegedly stable, non-hygroscopic L-carnitine salts (Table 1).
TABLE 1Conventional L-Carnitine Salts that are manufactured at commercialscales and available commerciallyL-Carnitine SaltDrawbackL-Carnitine acid fumarate (U.S. Pat. No.Not a source for both L-carnitine and4,602,039, Sigma-Tau)calcium.L-carnitine L-(+)-tartrate (U.S. Pat. No.Not a source for both L-carnitine and5,703,376, Lonza)calcium. Not a physiological organic acid.Acetyl L-carnitine galactarate (U.S.Not a source for both L-carnitine andPat. No. 5,952,379, Sigma-Tau)calcium. Galactarate is the anion of anunnatural polyhydroxy polybasic acid (i.e.,it is not a substance found in physiologicalsystems).L-carnitine magnesium citrate (U.S. Pat. No.Not a source for both L-carnitine and5,071,874, Lonza)calcium.L-Carnitine calcium galactarate and L-Not yet commercially available. Galactariccarnitine magnesium galactarate (Fassi,acid is an unnatural polyhydroxy polybasicWO 02/059075 A1)acid (i.e., it is not a substance found inphysiological systems).
When used as a dietary supplement and exogenous source of L-carnitine, gram quantities of conventional L-carnitine compounds may be ingested each day for extended periods of time. Likewise, gram quantities of calcium compounds may be ingested daily to provide exogenous calcium as a dietary supplement to promote bone development and prevent osteoporosis, for example. Women and children conventionally use both L-carnitine and calcium supplements having these dosage regimens. The chronic dosage amounts thus utilized are sufficiently sizeable that it is important to provide L-carnitine calcium compositions in which all components are either metabolized to innocuous products or do not accumulate and potentially cause toxicity.
The important physiological roles played by Ca2+ and L-carnitine and the various pathological disturbances or states induced by serious deficiencies of these substances have been known for decades.
Therefore, there is a significant unmet need for stable, non-hygroscopic sources of L-carnitine and calcium in order to allow the preparation of orally or intravenously administrable compositions to be used as sources of L-carnitine and calcium in all those situations wherein calcium and/or L-carnitine supplementation prevents the onset or reverses the course of deleterious effects brought about by their deficiency. The present invention addresses this significant unmet need.